Newer variants of progressive familial intrahepatic cholestasis

Abstract

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of disorders characterized by defects in bile secretion and presentation with intrahepatic cholestasis in infancy or childhood. The most common types include PFIC 1 (deficiency of FIC1 protein, ATP8B1 gene mutation), PFIC 2 (bile salt export pump deficiency, ABCB11 gene mutation), and PFIC 3 (multidrug resistance protein-3 deficiency, ABCB4 gene mutation). Mutational analysis of subjects with normal gamma-glutamyl transferase cholestasis of unknown etiology has led to the identification of newer variants of PFIC, known as PFIC 4, 5, and MYO5B related (sometimes known as PFIC 6). PFIC 4 is caused by the loss of function of tight junction protein 2 (TJP2) and PFIC 5 is due to NR1H4 mutation causing Farnesoid X receptor deficiency. MYO5B gene mutation causes microvillous inclusion disease (MVID) and is also associated with isolated cholestasis. Children with TJP2 related cholestasis (PFIC-4) have a variable spectrum of presentation. Some have a self-limiting disease, while others have progressive liver disease with an increased risk of hepatocellular carcinoma. Hence, frequent surveillance for hepatocellular carcinoma is recommended from infancy. PFIC-5 patients usually have rapidly progressive liver disease with early onset coagulopathy, high alpha-fetoprotein and ultimately require a liver transplant. Subjects with MYO5 B-related disease can present with isolated cholestasis or cholestasis with intractable diarrhea (MVID). These children are at risk of worsening cholestasis post intestinal transplant (IT) for MVID, hence combined intestinal and liver transplant or IT with biliary diversion is preferred. Immunohistochemistry can differentiate most of the variants of PFIC but confirmation requires genetic analysis.

Keywords: Progressive familial intrahepatic cholestasis, Tight junction protein, Hepatocellular carcinoma, Biliary diversion, Microvillous inclusion disease

Core Tip: Progressive familial intrahepatic cholestasis (PFIC) manifests with a varying spectrum of clinical features, with some variants progressing rapidly into end stage liver disease. Recently, newer variants of PFIC have been described including PFIC 4 due to tight junction protein 2 (TJP2) mutation, PFIC 5 due to NR1H4 mutation and MYO5B related cholestasis also sometimes known as PFIC 6. TJP2 related PFIC also has a risk of hepatocellular carcinoma. This article describes the pathogenesis and clinical features of the newer variants of PFIC.